Leptin was discovered when the gene mutation in the ob/ob mouse, an animal model of obesity, was identified. Leptin is a polypeptide of 167 amino acids that is encoded by the obese (ob) gene. Ob/ob mice make a defective leptin product and are extremely obese and hyperphagic. Since leptin administration causes a dramatic reduction in weight and food intake in these mice, it was hoped that leptin could be used to treat obesity in humans. As leptin is produced and secreted by fat cells, leptin levels are proportional to fat tissue mass and are high in obese humans. Exogenous leptin has limited effect in inducing weight loss, suggesting that obese humans have leptin resistance. Nevertheless, the discovery of leptin was pivotal for a number of reasons. It identified adipose tissue as an endocrine organ and was the first of the adiopocyte-derived hormones, later termed adipokines, to be recognized. It led to the discovery of a monogenic form of obesity in rodents and humans in which mutations in the leptin gene cause congenital leptin deficiency. Finally, it presented a form of treatment for patients with leptin gene mutations and patients with lipodystrophy. Our major effort has been in clinical trials of leptin therapy in lipodystrophy. Leptin levels are low in these patients and leptin replacement therapy results in a reduction in hemoglobin A1c, fasting blood glucose, triglyceride values, liver size, and liver function test abnormalities. Furthermore, in those patients who have normal reproductive organs, leptin therapy improves reproductive function. Thus, leptin therapy appears to have a major beneficial effect on the metabolic and endocrine abnormalities seen in these patients. In lipodystrophic patients, nonalcoholic steatohepatitis (NASH) is a common finding. Our studies have shown that leptin therapy not only reduces steatosis, but also decreases the severity of the NASH score, which largely measures the degree of oxidative stress. On the basis of our studies, the FDA approved leptin for the treatment of generalized lipodystrophy in February, 2014. This is the first novel therapy for extreme insulin resistance since the discovery of insulin over 85 years ago.